IN SILICO TOXIC EFFECTS OF 2-(4-TERT-BUTYLPHENYL) PROPANAL, 3-(4-TERT-BUTYLPHENYL)-2-METHYLPROPANAL AND LILAL MOLECULES AND PREGNANCY

Year 2025, Volume: 7 Issue: 1, 1 - 10, 30.04.2025

Bayram Furkan Coşkun , Neslihan Özdemir , Serap Yalcin Azarkan

https://doi.org/10.55895/sshs.1688179

Abstract

In our daily lives, we are exposed to many chemicals originating from products such as cosmetics, cleaning products, and food. These substances may be potential carcinogens and endocrine disruptors. In recent years, BMHCA (3-(4-(tert-butyl) phenyl)-2-methylpropanal, Lilial) and its derivatives have attracted much attention. These substances are generally used in products for fragrance purposes. BMHCA has been published in the EU Cosmetic Products Regulation and banned in cosmetic products offered in the EU and Northern Ireland markets. In this study, the toxic effects of 2-(4-tert-butylphenyl) propanal, 3-(4-tert-butylphenyl)-2-methylpropanal, and Lilal were determined by in silico analysis. According to the results obtained, it was determined that the molecules had moderate and high toxicity levels. The common features of all these compounds include their ability to cross the blood-brain barrier (BBB) at a high rate and their potential to be moderately to highly carcinogenic. Our study is a preliminary study and needs to be supported by in vitro and in vivo studies.

Keywords

BMHCA(Lilial) , Carcinogens , Obstetrics and Gynaecology , Pregnancy , Toxicity

References

• ACOG Committee Opinion No 575. Exposure to toxic environmental agents. Fertil Steril. 2013 Oct;100(4):931-4. doi: 10.1016/j.fertnstert.2013.08.043. PMID: 24070500; PMCID: PMC9060637.
• Api, A. M., Belsito, D., Biserta, S., Botelho, D., Bruze, M., Burton, G. A., ... & Tsang, S. (2020). RIFM fragrance ingredient safety assessment, pt-butyl-α-methylhydrocinnamic aldehyde, CAS Registry Number 80-54-6. Food and Chemical Toxicology, 141, 111430.
• Bernauer, U. et al. "SCCS OPINION ON the safety of Butylphenyl methylpropional (p-BMHCA) in cosmetic products-Submission II" SCCS/1591/17-Final version, https://health.ec.europa.eu/system/files/2021-08/sccs_o_213_0.pd (2019).
• Bialas, I., Zelent-Kraciuk, S., & Jurowski, K. (2023). The Skin Sensitisation of Cosmetic Ingredients: Review of Actual Regulatory Status. Toxics, 11(4), 392. https://doi.org/10.3390/toxics11040392
• Charles AK, Darbre PD. Oestrogenic activity of benzyl salicylate, benzyl benzoate and butylphenylmethylpropional (Lilial) in MCF7 human breast cancer cells in vitro. J Appl Toxicol. 2009 Jul;29(5):422-34. doi: 10.1002/jat.1429. PMID: 19338011.
• Di Sotto, A., Maffei, F., Hrelia, P., Di Giacomo, S., Pagano, E., Borrelli, F., & Mazzanti, G. (2014). Genotoxicity assessment of some cosmetic and food additives. Regulatory toxicology and pharmacology: RTP, 68(1), 16–22. https://doi.org/10.1016/j.yrtph.2013.11.003
• ECHA. Substance Infocard: 2-(4-tert butylbenzyl) propionaldehyde, https://echa.europa.eu/substance-information/-/substanceinfo/100.001.173 (2023).
• EFSA, C. (2011). Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2011. Scientific opinion on Flavouring group evaluation, 25.
• Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., & Patel, K. J. (2012). Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature, 489(7417), 571-575.
• Gore, A. C., Chappell, V. A., Fenton, S. E., Flaws, J. A., Nadal, A., Prins, G. S., Toppari, J., & Zoeller, R. T. (2015). EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocrine reviews, 36(6), E1–E150. https://doi.org/10.1210/er.2015-1010
• Heisterberg, M. V., Menné, T., & Johansen, J. D. (2011). Contact allergy to the 26 specific fragrance ingredients to be declared on cosmetic products in accordance with the EU cosmetics directive. Contact Dermatitis, 65(5), 266-275.
• Hendryx, M., & Luo, J. (2018). Children’s environmental chemical exposures in the USA, NHANES 2003–2012. Environmental Science and Pollution Research, 25, 5336-5343. https://tox.charite.de/protox3/index.php?site=compound_search_similarity(Son erişim: 16.04.2025)
• Jablonská, E., Míchal, Z., Křížkovská, B., Strnad, O., Tran, V. N., Žalmanová, T., Petr, J., Lipov, J., & Viktorová, J. (2023). Toxicological investigation of lilial. Scientific reports, 13(1), 18536. https://doi.org/10.1038/s41598-023-45598-y
• Kobets, T., Duan, J. D., Brunnemann, K. D., Iatropoulos, M. J., Etter, S., Hickey, C., ... & Williams, G. M. (2018). In ovo testing of flavor and fragrance materials in Turkey Egg Genotoxicity Assay (TEGA), comparison of results to in vitro and in vivo data. Food and Chemical Toxicology, 115, 228-243.
• Lalko, J., Isola, D., & Api, A. M. (2004). Ethanol and diethyl phthalate: vehicle effects in the local lymph node assay. International Journal of Toxicology, 23(3), 171-177.
• Langton, K., Patlewicz, G. Y., Long, A., Marchant, C. A., & Basketter, D. A. (2006). Structure–activity relationships for skin sensitization: recent improvements to Derek for Windows. Contact Dermatitis, 55(6), 342-347.
• No, A. C. O. (2013). Exposure to toxic environmental agents. Fertility and sterility, 100(4), 931-934.
• Özdemir, R., Şahin, S., & Arıöz, A. (2022). Gebelikte Kozmetik Kullanımı ve Sağlık Riskleri. Hemşirelik Bilimi Dergisi, 5(1), 30-37.
• Roberts, D. W., Patlewicz, G., Kern, P. S., Gerberick, F., Kimber, I., Dearman, R. J., ... & Aptula, A. O. (2007). Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization. Chemical Research in Toxicology, 20(7), 1019-1030.
• Sade, G., & Özkan, H. (2020). Kozmetik ürünlerdeki bazı kimyasalların gebe, fetüs ve yenidoğan sağlığına etkisi. Jinekoloji-Obstetrik ve Neonatoloji Tıp Dergisi, 17(3), 473-477.
• SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation 11th Revision SCCS/1628/21. 2021. [(accessed on 27 March 2023)]. Available online: https://health.ec.europa.eu/system/files/2022-08/sccs_o_250.pdf [PubMed]
• UE Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products. 2009. [(accessed on 27 March 2023)]. Available online: http://data.europa.eu/eli/reg/2009/1223/2022-12-17
• Usta, J., Hachem, Y., El-Rifai, O., Bou-Moughlabey, Y., Echtay, K., Griffiths, D., ... & Makki, R. F. (2013). Fragrance chemicals lyral and lilial decrease viability of HaCat cells’ by increasing free radical production and lowering intracellular ATP level: protection by antioxidants. Toxicology in Vitro, 27(1), 339-348.
• Varshavsky, J., Smith, A., Wang, A., Hom, E., Izano, M., Huang, H., Padula, A., & Woodruff, T. J. (2020). Heightened susceptibility: A review of how pregnancy and chemical exposures influence maternal health. Reproductive toxicology (Elmsford, N.Y.), 92, 14–56. https://doi.org/10.1016/j.reprotox.2019.04.004
• Wang, A., Padula, A., Sirota, M., & Woodruff, T. J. (2016). Environmental influences on reproductive health: the importance of chemical exposures. Fertility and sterility, 106(4), 905-929.